The Hsp90 Chaperone Machinery

Abstract

Hsp90 was originally identified as one of several conserved heat shock proteins. Like the other major classes of heat shock proteins, Hsp90 exhibits general protective chaperone properties, such as preventing the unspecific aggregation of non-native proteins (1Wiech H. Buchner J. Zimmermann R. Jakob U. Nature. 1992; 358: 169-170Crossref PubMed Scopus (417) Google Scholar). However, Hsp90 seems to be more selective than the other promiscuous general chaperones, as it preferentially interacts with a specific subset of the proteome (2Picard D. CMLS Cell. Mol. Life Sci. 2002; 59: 1640-1648Crossref PubMed Scopus (645) Google Scholar). Another specific feature of Hsp90 is its regulatory role of inducing conformational changes in folded, native-like substrate proteins that lead to their activation or stabilization (3Jakob U. Lilie H. Meyer I. Buchner J. J. Biol. Chem. 1995; 270: 7288-7294Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar). Recently, the three-dimensional structures of full-length Hsp90 from Escherichia coli, yeast, and the endoplasmic reticulum were solved (4Shiau A.K. Harris S.F. Southworth D.R. Agard D.A. Cell. 2006; 127: 329-340Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 5Ali M.M. Roe S.M. Vaughan C.K. Meyer P. Panaretou B. Piper P.W. Prodromou C. Pearl L.H. Nature. 2006; 440: 1013-1017Crossref PubMed Scopus (683) Google Scholar, 6Dollins D.E. Warren J.J. Immormino R.M. Gewirth D.T. Mol. Cell. 2007; 28: 41-56Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 7Pearl L.H. Prodromou C. Annu. Rev. Biochem. 2006; 75: 271-294Crossref PubMed Scopus (875) Google Scholar). Together with sequence data, these showed that, although Hsp90 maintained its general domain structure from bacteria to man, distinct changes seem to have adapted Hsp90 to the more complex protein environment of the eukaryotic cell. Concomitant with the occurrence of a long charged linker connecting the N- 3The abbreviations used are: N-domain, N-terminal domain; M-domain, middle domain; SHR, steroid hormone receptor; TPR, tetratricopeptide repeat; PPIase, peptidylprolyl cis/trans-isomerase; eNOS, epithelial nitric-oxide synthase. 3The abbreviations used are: N-domain, N-terminal domain; M-domain, middle domain; SHR, steroid hormone receptor; TPR, tetratricopeptide repeat; PPIase, peptidylprolyl cis/trans-isomerase; eNOS, epithelial nitric-oxide synthase. and M-domains, the eukaryotic protein exhibits an extension of the C-terminal domain, which includes the conserved amino acid motif MEEVD at the C terminus (8Chen S. Sullivan W.P. Toft D.O. Smith D.F. Cell Stress Chaperones. 1998; 3: 118-129Crossref PubMed Scopus (166) Google Scholar). This region serves as the major interaction site for a cohort of co-chaperones (Table 1) (9Richter K. Meinlschmidt B. Buchner J. Buchner J. Kiefhaber T Protein Folding Handbook. Wiley-VCH Verlag GmbH & Co., Weinheim, Germany2005: 768-829Crossref Scopus (1) Google Scholar), which apparently support Hsp90 in the folding and activation of its substrate proteins in eukaryotes. In this review, we summarize the current knowledge on the functional principles of this molecular machine, including the ATP-driven chaperone cycle of Hsp90 and its regulation by co-chaperones and post-translational modifications.TABLE 1Selected Hsp90 cofactors Open table in a new tab Hsp90 is a flexible dimer. Each monomer consists of three domains: the N-domain, connected by a long linker sequence (in eukaryotes) to an M-domain, which is followed by a C-terminal dimerization domain (Fig. 1). The N-domain possesses a deep ATP-binding pocket (10Prodromou C. Roe S.M. O'Brien R. Ladbury J.E. Piper P.W. Pearl L.H. Cell. 1997; 90: 65-75Abstract Full Text Full Text PDF PubMed Scopus (1098) Google Scholar), where ATP is bound in an unusual kinked manner. ATP hydrolysis by Hsp90 is rather slow: Hsp90 from yeast hydrolyzes one molecule of ATP every 1 or 2 min (11Panaretou B. Prodromou C. Roe S.M. O'Brien R. Ladbury J.E. Piper P.W. Pearl L.H. EMBO J. 1998; 17: 4829-4836Crossref PubMed Scopus (610) Google Scholar, 12Scheibel T. Weikl T. Buchner J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1495-1499Crossref PubMed Scopus (229) Google Scholar), and human Hsp90 hydrolyzes one molecule of ATP every 20 min (0.04 min–1) (13McLaughlin S.H. Smith H.W. Jackson S.E. J. Mol. Biol. 2002; 315: 787-798Crossref PubMed Scopus (210) Google Scholar). The ATPase activity is essential for the function of Hsp90 in yeast (11Panaretou B. Prodromou C. Roe S.M. O'Brien R. Ladbury J.E. Piper P.W. Pearl L.H. EMBO J. 1998; 17: 4829-4836Crossref PubMed Scopus (610) Google Scholar, 14Obermann W.M. Sondermann H. Russo A.A. Pavletich N.P. Hartl F.U. J. Cell Biol. 1998; 143: 901-910Crossref PubMed Scopus (479) Google Scholar). The slow hydrolysis suggests that complex conformational rearrangements of Hsp90 are coupled to the ATPase reaction and that these represent the rate-limiting step of the enzyme. The first steps of these conformational changes were elucidated recently in detail (15Richter K. Moser S. Hagn F. Friedrich R. Hainzl O. Heller M. Schlee S. Kessler H. Reinstein J. Buchner J. J. Biol. Chem. 2006; 281: 11301-11311Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar): upon ATP binding, a short segment of the N-domain called the “ATP lid” changes its position and flaps over the binding pocket (Fig. 1, steps 2 and 3). This releases a short N-terminal segment from its original position (16Richter K. Reinstein J. Buchner J. J. Biol. Chem. 2002; 277: 44905-44910Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). In a subsequent reaction, this segment binds to the respective N-domain of the other subunit in the dimer, producing a strand-swapped, transiently dimerized N-terminal conformation (step 3) (5Ali M.M. Roe S.M. Vaughan C.K. Meyer P. Panaretou B. Piper P.W. Prodromou C. Pearl L.H. Nature. 2006; 440: 1013-1017Crossref PubMed Scopus (683) Google Scholar, 15Richter K. Moser S. Hagn F. Friedrich R. Hainzl O. Heller M. Schlee S. Kessler H. Reinstein J. Buchner J. J. Biol. Chem. 2006; 281: 11301-11311Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). These N-terminal rearrangements result in further conformational changes throughout the entire Hsp90 dimer leading to a twisted and compacted dimer, in which N- and M-domains associate and the distance between M-domains is shortened by 40 Å (5Ali M.M. Roe S.M. Vaughan C.K. Meyer P. Panaretou B. Piper P.W. Prodromou C. Pearl L.H. Nature. 2006; 440: 1013-1017Crossref PubMed Scopus (683) Google Scholar). The association of N- and M-domains completes the active site of this “split ATPase” (step 4). Recently, a similar progression of steps was shown to occur also for the endoplasmic homolog Grp94 (17Frey S. Leskovar A. Reinstein J. Buchner J. J. Biol. Chem. 2007; 282: 35612-35620Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar), mitochondrial TRAP1 (6Dollins D.E. Warren J.J. Immormino R.M. Gewirth D.T. Mol. Cell. 2007; 28: 41-56Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 18Leskovar, A., Wegele, H., Werbeck, N. D., Buchner, J., and Reinstein, J. (2008) 283, 11677–11688Google Scholar), and human Hsp90 (19Richter K. Soroka J. Skalniak L. Leskovar A. Hessling M. Reinstein J. Buchner J. J. Biol. Chem. 2008; 283: 17757-17765Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Therefore, the scenario outlined above seems to be the ubiquitously conserved ATPase mechanism for Hsp90. Interestingly, the unusual way in which ATP is bound by Hsp90 is perfectly mimicked by some natural compounds, such as geldanamycin and radicicol. These are highly specific and potent inhibitors of the Hsp90 ATPase (20Roe S.M. Prodromou C. O'Brien R. Ladbury J.E. Piper P.W. Pearl L.H. J. Med. Chem. 1999; 42: 260-266Crossref PubMed Scopus (871) Google Scholar), blocking the maturation of substrate proteins and eventually resulting in their degradation (21Whitesell L. Mimnaugh E.G. De Costa B. Myers C.E. Neckers L.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8324-8328Crossref PubMed Scopus (1310) Google Scholar). As several Hsp90 substrate proteins are kinases, which can be deregulated in the development of cancer, derivatives of Hsp90 inhibitors are currently being investigated as anticancer therapeutics at the stage of clinical trials (22Sharp S. Workman P. Adv. Cancer Res. 2006; 95: 323-348Crossref PubMed Scopus (269) Google Scholar). Current models assume that the conformational changes associated with ATP hydrolysis are required for reaching or maintaining an activated state of a substrate protein. In well studied examples such as the SHRs, several cofactors interact with Hsp90 in a sequential manner to assemble a functional chaperone machinery (23Pratt W.B. Toft D.O. Exp. Biol. Med. (Maywood). 2003; 228: 111-133Crossref PubMed Scopus (1239) Google Scholar, 24Smith D.F. Mol. Endocrinol. 1993; 7: 1418-1429Crossref PubMed Scopus (251) Google Scholar). The basis for this ordered succession of different assemblies can now be rationalized, as it turned out that several Hsp90 cofactors display a strong binding preference for specific Hsp90 conformations. The loading of an SHR onto Hsp90 requires the cooperation of Hsp90 with the chaperone Hsp70 and its cofactor Hsp40 (25Smith D.F. Sullivan W.P. Marion T.N. Zaitsu K. Madden B. McCormick D.J. Toft D.O. Mol. Cell. Biol. 1993; 13: 869-876Crossref PubMed Scopus (246) Google Scholar). Moreover, both chaperones become physically linked by an adaptor protein called Hop/Sti1 (Table 1). This co-chaperone binds via small helical TPR domains to the C-terminal ends of Hsp70 and Hsp90 (26Scheufler C. Brinker A. Bourenkov G. Pegoraro S. Moroder L. Bartunik H. Hartl F.U. Moarefi I. Cell. 2000; 101: 199-210Abstract Full Text Full Text PDF PubMed Scopus (991) Google Scholar). It seems that Hsp70 stabilizes the SHR in a conformation that can be recognized and bound by Hsp90. However, experimental evidence for this notion is largely lacking. How the substrate in this complex is transferred from Hsp70 to Hsp90 is also still unclear. It might be that the bridging by Hop/Sti1 selects for Hsp90 molecules in a conformation competent for substrate binding in addition to increasing the local concentration of Hsp70 and Hsp90. For the progression of the chaperone cycle, empty Hsp70 and Hop/Sti1 have to dissociate, and other co-chaperones such as specific PPIases and p23/Sba1 enter the complex (Table 1) (24Smith D.F. Mol. Endocrinol. 1993; 7: 1418-1429Crossref PubMed Scopus (251) Google Scholar). These PPIases also possess a TPR domain, which binds to the C-terminal end of Hsp90. The second cofactor, p23/Sba1, associates with the N-terminally dimerized conformation of Hsp90 (27Prodromou C. Panaretou B. Chohan S. Siligardi G. O'Brien R. Ladbury J.E. Roe S.M. Piper P.W. Pearl L.H. EMBO J. 2000; 19: 4383-4392Crossref PubMed Google Scholar, 28Richter K. Walter S. Buchner J. J. Mol. Biol. 2004; 342: 1403-1413Crossref PubMed Scopus (119) Google Scholar), making it likely that the dramatic conformational rearrangement from the open to the closed state of Hsp90 occurs at this stage of the Hsp90 chaperone cycle (Fig. 1, steps 3 and 4). This closed conformation is metastable and upon ATP hydrolysis returns to the open state (Fig. 1, step 5) (28Richter K. Walter S. Buchner J. J. Mol. Biol. 2004; 342: 1403-1413Crossref PubMed Scopus (119) Google Scholar). The bound substrate protein dissociates in turn from Hsp90, permitting a new round of the cycle. The first steps of the cycle for the maturation of signaling kinases is a variation of the scheme described above. Here, the kinase-specific Hsp90 cofactor Cdc37 seems to associate with substrate kinases in their inactive forms first. This complex may then be loaded onto Hsp90 (29Kimura Y. Rutherford S.L. Miyata Y. Yahara I. Freeman B.C. Yue L. S. 1997; PubMed Scopus Google Scholar). The steps are It may be that also for kinases, and Hop/Sti1 are required A.K. Cell Biol. 2007; 17: Full Text Full Text PDF PubMed Scopus Google Scholar). Cdc37 the ATPase of Hsp90 G. Panaretou B. Meyer P. S. Piper P.W. Pearl L.H. Prodromou C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), it is to that a of the ATPase substrate onto Hsp90 in to more than a distinct Hsp90 cofactors have identified (9Richter K. Meinlschmidt B. Buchner J. Buchner J. Kiefhaber T Protein Folding Handbook. Wiley-VCH Verlag GmbH & Co., Weinheim, Germany2005: 768-829Crossref Scopus (1) Google Scholar). is by other chaperone Hsp90 with (Table 1). The major of these is the TPR which the proteins and the (Table 1). of these cofactors the activation of a of substrate proteins. In this the cofactor shown to in development the of Brinker A. Hartl F.U. 2002; PubMed Scopus Google Scholar), and in complex with the protein from the N. C. W.M. Res. PubMed Scopus Google or the 1999; PubMed Scopus Google Scholar). It to be these cofactors are highly or are the first Interestingly, in yeast, cofactors of the Hsp90 are essential for (in addition to These are Cdc37 and (29Kimura Y. Rutherford S.L. Miyata Y. Yahara I. Freeman B.C. Yue L. S. 1997; PubMed Scopus Google Scholar, J. Mol. Cell. Biol. 1998; PubMed Google Scholar, Mol. Cell. Biol. 1998; PubMed Google Scholar). shown to associate with both Hsp90 and to the of a TPR domain, can be O. H. K. Buchner J. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The function of Hsp90 is several that its As the ATPase activity is to slow conformational changes of the segment the In addition to the ATPase activity of Hsp90 is by several Another of cofactors substrate the ATPase the activity of Hsp90 is also by post-translational of the cofactors of Hsp90 its ATPase activity by preferentially with a specific conformation of Hsp90. p23/Sba1 binds to the ATPase domain and stabilizes the N-terminally dimerized conformation at the stage of the ATPase cycle (Fig. 1) (28Richter K. Walter S. Buchner J. J. Mol. Biol. 2004; 342: 1403-1413Crossref PubMed Scopus (119) Google Scholar, A. I. Sullivan B. N. Toft D.O. Proc. Natl. Acad. Sci. U. S. 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Southworth D.R. Agard D.A. Cell. 2006; 127: 329-340Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 5Ali M.M. Roe S.M. Vaughan C.K. Meyer P. Panaretou B. Piper P.W. Prodromou C. Pearl L.H. Nature. 2006; 440: 1013-1017Crossref PubMed Scopus (683) Google Scholar, 6Dollins D.E. Warren J.J. Immormino R.M. Gewirth D.T. Mol. Cell. 2007; 28: 41-56Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). In to chaperones and from of Hsp90 to R. M. Biochem. Sci. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), it was that the substrate protein may be by the Hsp90 dimer. This notion is in with the in which is to a substrate protein between the Hsp90 The first of the structure of an complex from and of Hsp90 in complex with the and the co-chaperone In this the substrate is bound in a highly to the and the N-domain of one the co-chaperone Cdc37 between the C.K. U. F. M.M. Prodromou C. Pearl L.H. Mol. Cell. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). this association is the for kinases and this can be for other substrate proteins to be the of ATP and associated conformational changes of Hsp90 to be solved other of the Hsp90 machinery are to These substrate and for of of in and in be required to these we a more of the of this molecular machine, we can to specific substrate proteins, and of regulation and post-translational the and for on the